Abstract

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK. Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. We have developed reduced-charge oligonucleotides containing artificial LNA-amide linkages which have improved gymnotic cell uptake, RNA affinity, stability and potency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies highlight the therapeutic potential of this technology. The concept is also being tested in ASOs.